The great Roman natural scientist Gaius Plinius Secundus (Pliny the Elder) first described Indian Ocean sea hare of the genus Dolabella around 60 A.D. (The Romans first designated Mollusca of the family Aplysidae as sea hares because of the similarity between the ears of a hare and the auriculate tentacles of these gastropods). However, a consideration of the potential of the Indian Ocean Dolabella with respect to modern medical problems is only of recent origin. For example, see the following patents which are hereby incorporated by reference: U.S. Pat. No. 4,414,205, Nov. 8, 1983, Dolastatins 1-3; U.S. Pat. No. 4,486,414, Dec. 4, 1984, Dolastatins A and B; U.S. Pat. No. 4,816,444, Mar. 28, 1989, Dolastatin 10; U.S. Pat. No. 4,879,278, Nov. 7, 1989, Dolastatin 15; U.S. Pat. No. 4,986,988, Jun. 22, 1991, Dolastatin 13 and Dehydrodolastatin 13; and U.S. Pat. No. 5,138,036, Aug. 11, 1992, Dolastatin 14. The aforementioned Dolastatins may correspond to D. auricularia constituents (See: 1969 Ph.D. dissertation of M. Watson. U. of Hawaii, "Some Aspects of the Pharmacology, Chemistry and Biology of the Midgut Gland Toxins of Some Hawaiian Sea Hares, especially Dolabella auricularia and Aplysia pulmonica", University Microfilms Inc., Ann Arbor, Mich.)
The biological properties exhibited by the Dolabella auricularia have been pursued for centuries, but it was only in 1972 that this laboratory found Indian Ocean specimens of this sea hare which yielded extracts that proved effective (over 100% increase in life span) against the U.S. National Cancer Institute's (NCI) murine P388 lymphocytic leukemia (PS system). Subsequently, the Cancer Research Institute at Arizona State University, Tempe, Ariz., succeeded in isolating many new (and powerful) cell growth inhibitory and/or antineoplastic peptides from Dolabella auricularia by using solvent separation techniques to fractionate these peptides in combination with bioassaying the fractionated aliquots for antineoplastic activity. Because the sea hare yields only very small quantities of antineoplastic substances (about 1 mg each from 100 kg), isolating and elucidating the structure of these peptides is exceptionally challenging.
Of the early work, Dolastatin 1 was found to be the most active (lowest dose) antineoplastic substance (33% cure rate against the NCI murine B16 melanoma at 11 pg/kg) known in its time. Later another substance was isolated and determined to be a unique linear pentapeptide and was denominated "Dolastatin 10". Dolabella auricularia antineoplastic constituent appeared to be the most active (lowest dose) antineoplastic substance found up to its time. In practice, Dolastatin 10 showed a 17-67% curative response at 3.25-26 .mu.g/kg against the National Cancer Institute ("NCI") human melanoma xenograph (nude mouse), 42-138% life extension at 1.44-11.1 .mu.g/kg using the B16 melanoma and 69-102% life extension at 1-4 .mu.g/kg against the PS leukemia (ED.sub.50 =4.6.times.10.sup.5 .mu.g/ml). In contrast, Dolastatin 14 is strongly active against NCI's P388 lymphocytic leukemia (PS System) (See: Schmidt et al, Experienta, 1978, 37, 659-660) cell line with ED.sub.50 of 0.0018 .mu.g/ml. The PS System is generally accepted as an excellent predictor of activity against various types of human cancer (See: Vendetti et al, Lloydia, 30,332 et seq. (1967) and references cited therein).